Project Summary The pathophysiology of Obsessive Compulsive Disorder (OCD) is associated with dysfunction in prefrontal cortical and basal-ganglia circuits, in particular the dorsal anterior cingulate cortex (dACC), orbital frontal cortex (OFC), ventrolateral prefrontal cortex (vlPFC) and dorsal striatum. These areas are linked to regions involved in both emotion (amygdala (amyg) and ventromedial PFC (vmPFC)) and higher cognitive and motor control (dorsolateral PFC (dlPFC) and presupplementary motor cortex (pSMA)), placing them in a pivotal position for bottom-up and top-down control for adapting behaviors appropriately. The dACC, vlPFC, and OFC fibers are connected by the cingulum bundle (CB), corpus callosum (CC) and uncinate fasciculus (UF). These white matter (WM) bundles, along with the internal capsule (IC) also show abnormalities in OCD. The overall goal of P1 is to determine the connectivity between the dACC, vlPFC, OFC, and striatum, and the amyg/vmPFC, and the dlPFC/ pSMA. We will use these data to explore connectivity abnormalities in OCD and the effects of noninvasive stimulation and cingulotomy on the WM. Our first hypothesis is that within the dACC, OFC, vlPFC, and striatum, there are specific regions (referred to as critical nodes) that contain converging terminal fields from each other, and from the amyg and/or vmPFC, and from the dlPFC and/or pSMA. These critical nodes would provide an anatomical substrate for modulation between emotional and cognitive systems. Our second hypothesize is that the abnormalities in the WM found in OCD will be located within specific WM segments that connect the critical nodes. Aim 1 will determine where critical nodes are located within the dACC, vlPFC, and OFC and aim 2 will segment the CB, CC, UF, and IC based on where node connections travel. Aims 1 and 2 combine tracer experiments and diffusion MRI (dMRI) animals and dMRI in humans to locate the nodes and segment the WM. Aim 3 will use the segmentation of WM is to evaluate more specifically connectivity differences between OCD and healthy subjects and changes due to neuromodulation. The combination of anatomical and dMRI experiments will provide a translational link for understanding the structural underpinnings of connectivity changes associated with OCD.